Project Summary/Abstract Currently, 30% of adults in the U.S. are obese, with the prevalence of obesity rising each year (CDC BRFSS, 2012). In 2011, the NIH released a strategic plan for obesity research to ?encourage the research community to examine the epidemic of obesity from diverse perspectives?. The proposed work directly addresses this need by using novel approaches to understand the neural mechanisms underlying enhanced cue-triggered food-seeking in obesity-prone and obese rats. In people, exposure to cues associated with food (food cues), like the scent of baking pastries or a blinking bakery sign, can increase craving for food and the increase the amount of food consumed (Fedoroff et al., 1997, Soussignan et al., 2012). Obese people are more susceptible to these motivational effects of food cues, which contributes to their weight gain (e.g., Stice et al., 2012). Our long-term goal is to understand the neurobiological and behavioral mechanisms governing motivation for food induced by food cues in order to prevent and treat obesity. Exposure to food-cues increases the fMRI BOLD signal in the nucleus accumbens (NAc) more strongly in obese vs. non-obese people (Stoeckel et al., 2008). Importantly, in normal weight individuals the magnitude of food cue induced activation of the NAc predicts future weight gain (Demos et al., 2012) and in overweight people it predicts difficulty with weight loss (Murdaugh, 2012; Jensen & Kirwan, 2015). This enhanced NAc response may be driven by glutamate transmission, as AMPA type glutamate receptors (AMPAR) provide the main source of excitation to the NAc, and the NAc plays critical roles in the ability of food cues to motivate behavior in non-obese rats (Kelley, 2004; Everitt and Robbins, 2005; Crombag et al., 2008; Corbit and Balleine, 2011). However, to date, no studies have examined NAc glutamate transmission in any preclinical model of obesity. Our preliminary data show that in obesity-prone rats food cues more strongly invigorate food-seeking behaviors than in obesity-resistant rats. Additionally we have separately demonstrated that eating a sugary-fatty ?junk-food? diet increases NAc surface levels of AMPARs. This suggests that obesity- prone rats might be more sensitive to experience-induced glutamatergic plasticity in the NAc. We will combine rodent models of obesity susceptibility and models of diet-induced obesity with behavioral, biochemical, pharmacological and DREADD techniques to determine the contribution of glutamatergic transmission in the NAc to enhanced motivation for food-cues in obesity-prone and obese individuals. This work will open new avenues for prevention and treatment by providing a richer understanding of the neurobehavioral differences driving enhanced cue-triggered motivation for food in obesity-prone and obese individuals.